Although methamphetamine has long been endemic to the Portland, Oregon region, its use has reached epidemic proportions nationally. Several studies have reported poor retention of stimulant abusors entering treatment, consistent with the 50% rate of our outpatient clinic. Unfortunately, there is no clinically approved medication to alleviate the severe aversive symptoms that accompany early abstinence from methamphetamine. Recent studies in cocaine abusers entering community day hospital treatment have shown that the beta antagonist propranolol decreases these aversive symptoms while increasing retention and abstinence rates. Hospitalized methamphetamine abusers entering outpatient treatment upon discharge, have comparable or greater amounts of aversive symptomatology. Preclinical stress induced reinstatement studies (in animals whose prior self administration is extinguished pior to stress) hypothesize that beta blockers protect against stress induced relapse. The purpose of the current grant is translational research testing this preclinical hypothesis as well as extending its application from cocaine to methamphetamine in two eighty patient double blind inpatient initiated eight week outpatient trials. Since the preclinical studies model relapse in abstinent patients all patients will be enrolled immediately after a recent hospitalization. Clinical Trial I will evaluate carvedilol, a beta antagonist with additional neuroprotective properties and alpha antagonist properties (believed to be safer in those patients who relapse to methamphetamine while on study medication). In Clinical Trial II, the goal will be translational research based on findings from Years 1-2 utilizing a cholinergic medication identified by Scientific Component 1. In addition, patients will undergo, after four weeks of study medication, a human laboratory evaluation of stressor responsivity. It has been hypothesized that increased stress responsivity is a long term neuroadaptation to drug abuse that may permanently increase the risk of stress-induced relapse.